Proteolysis-targeting chimera against NR4A1 for cancer immunotherapy

Abstract Modulating tumor-infiltrating immune cells is the key mission for development of cancer immunotherapy. Based on recent literature and our bioinformatic analysis, nuclear receptor subfamily 4 group A member 1 (NR4A1) an ideal target immunotherapy due to its important role in T cell exhaustion, regulatory (Treg) function. Here we targets NR4A1 via proteolysis-targeting chimeric (PROTAC) technology, expecting achieve activation clearance. We designed synthesized over 80 PROTACs based several reported ligands, such as celastrol. found that celastrol-based achieved effective degradation protein NR4A1. studied therapeutic efficiency lead NR-V04, a celastrol- von Hippel-Lindau (VHL)-based PROTAC. As expected, confirmed NR-V04-induced through uniquitin proteasome system with tenery complex formation among NR4A1, VHL NR-V04. The NR-V04 exhibits outstanding pharmacokinetics effectively inhibits tumor growth at low dose, 1.8mg/kg twice week, B16F10, Yummer 1.7, MC38 mouse models. proved significantly enhances anti-tumor immunity seemingly distinct mechanisms tumor-dependent manner. For example, induces expansion B reduction myeloid-derived suppressor (MDSC) B16F10; Tregs, induction CD8 effector population 1.7 tumors. did not find obvious toxicity these doses up 2 months. Therefore, or other better ones under test have potential translation novel immunotherapeutic strategy. BC200100 - “Developing Novel PROTAC-Based Degrader Breast Cancer Therapy” (DEPARTMENT OF THE ARMY)